Tetrahydropyridoethers

ABSTRACT

Compounds of formula (1) in which the substituents have the meanings mentioned in the description, are suitable for the prevention and treatment of gastrointestinal diseases.

FIELD OF APPLICATION OF THE INVENTION

[0001] The invention relates to novel compounds which are used in thepharmaceutical industry as active compounds for the production ofmedicaments.

KNOWN TECHNICAL BACKGROUND

[0002] U.S. Pat. No. 4,468.400 describes tricyclic,imidazo[1,2-a]pyridines having various ring systems fused onto theimidazopyridine parent structure, which are said to be suitable for thetreatment of peptic ulcer disorders.

DESCRIPTION OF THE INVENTION

[0003] The invention relates to compounds of the formula I

[0004] in which

[0005] R1 is methyl or hydroxymethyl.

[0006] one of the substituents R2a and R2b is hydrogen and the other ishydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy.

[0007] one of the substituents R3a and R3b is hydrogen and the other ishydroxy, methyl, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,

[0008] where R2a or R2b on the one hand and R3a or R3b on the other handare not simultaneously hydroxy, and their salts.

[0009] Suitable salts of compounds of the formula I are especially allacid addition salts. Particular mention may be made of thepharmacologically tolerable salts of the inorganic and organic addscustomarily used in pharmacy. Those suitable are water-soluble andwater-insoluble add addition salts with acids such as, for example,hydrochloric acid, hydrobromic acid, phosphoric acid, nitric add,sulfuric acid, acetic add, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzyl)benzoic acid, butyric acid, sulfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic add, toluenesulfonicacid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where theacids are employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

[0010] Pharmacologically intolerable salts which can be initiallyobtained as process products, for example in the preparation of thecompounds according to the invention on an industrial scale, areconverted into pharmacologically tolerable salts by processes known tothe person skilled in the art.

[0011] According to expert's knowledge the compounds of the invention aswell as their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore all solvates and in particular all hydrates of thecompounds of formula I as well as all solvates and in particular allhydrates of the salts of the compounds of formula I.

[0012] The compounds of the formula I have three chiral centers. Theinvention relates to all eight conceivable stereoisomers in any desiredmixing ratio with one another, including the pure enantiomers, which area preferred subject of the invention.

[0013] A preferred embodiment of the invention are compounds of theformula I★

[0014] in which

[0015] R1 is methyl or hydroxymethyl,

[0016] one of the substituents R2a and R2b is hydrogen and the other ishydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,

[0017] one of the substituents R3a and R3b is hydrogen and the other ishydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,

[0018] where R2a or R2b on the one hand and R3a or R3b on the other handare not simultaneously hydroxy, and their salts.

[0019] An embodiment (embodiment a) of the invention are compounds ofthe formula I★,

[0020] in which

[0021] R1 is methyl,

[0022] one of the substituents R2a and R2b is hydrogen end the other ismethoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,

[0023] one of the substituents R3a an R3b is hydrogen and the other ishydroxy, and their salts.

[0024] A further embodiment (embodiment b) of the invention arecompounds of the formula I★,

[0025] in which

[0026] R1 is methyl,

[0027] one of the substituents R2a and R2b is hydrogen and the other ishydroxy.

[0028] one of the substituents R3a and R3b is hydrogen and the other ismethoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,

[0029] and their salts.

[0030] A further embodiment (embodiment c) of the invention arecompounds of the formula I★,

[0031] in which

[0032] R1 is methyl,

[0033] one of the substituents R2a end R2b is hydrogen and the other ismethoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,

[0034] one of the substituents R3a and R3b is hydrogen and the other ismethoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,

[0035] and their salts.

[0036] A further embodiment (embodiment d) of the invention arecompounds of the formula I★,

[0037] in which

[0038] R1 is hydroxymethyl,

[0039] one of the substituents R2a and R2b is hydrogen and the other ismethoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,

[0040] one of the substituents R3a and R3b is hydrogen and the other ishydroxy, end their salts.

[0041] A further embodiment (embodiment a) of the invention arecompounds of the formula I★,

[0042] in which

[0043] R1 is hydroxymethyl,

[0044] one of the substituents R2a and R2b is hydrogen and the other ishydroxy,

[0045] one of the substituents R3a and R3b is hydrogen and the other ismethoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,

[0046] and their salts.

[0047] A further embodiment (embodiment f) of the invention arecompounds of the formula I*,

[0048] in which

[0049] R1 is hydroxymethyl,

[0050] one of the substituents R2a and R2b is hydrogen and the other ismethoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,

[0051] one of the substituents R3a and R3b is hydrogen and the other ismethoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,

[0052] and their salts.

[0053] Preferred compounds of the embodiments a to f are those, in whichR3b is hydrogen.

[0054] Particularly preferred compounds of the embodiments a to f arethose, in which R2a and R3b are hydrogen.

[0055] Preferred compounds within the scope of the invention are thoseof embodiment a, which can be characterized by the formula I★

[0056] in which

[0057] one of the substituents Ra and Rb is hydrogen and the other ismethoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy

[0058] and their salts.

[0059] Particularly preferred compounds of embodiment a are those offormula I★, in which

[0060] Ra is hydrogen and

[0061] Rb is methoxy, ethoxy, isopropoxy, methoxyethoxy ormethoxypropoxy,

[0062] an their salts.

[0063] With the aid of the general formula I★, the following exemplarypreferred compounds according to the invention may actually be mentionedby means of the substituent meanings for R1, R2a, R2b, R3a and R3b inthe following Table 1 (Tab. 1): TABLE 1 R1 R2a R2b R3a R3b CH₃ H OCH₃ OHH CH₃ H OC₂H₅ OH H CH₃ H OCH(CH₃)₂ OH H CH₃ H OCH₂CH₂OCH₃ OH H CH₃ HOCH₂CH₂CH₂OCH₃ OH H CH₃ H OH OCH₃ H CH₃ H OH OC₂H₅ H CH₃ H OH OCH(CH₃)₂H CH₃ H OH OCH₂CH₂OCH₃ H CH₃ H OH OCH₂CH₂CH₂OCH₃ H CH₃ H OCH₃ OCH₃ H CH₃H OC₂H₅ OC₂H₅ H CH₃ H OCH(CH₃)₂ OCH(CH₃)₂ H CH₃ H OCH₂CH₂OCH₃OCH₂CH₂OCH₃ H CH₃ H OCH₂CH₂CH₂OCH₃ OCH₂CH₂CH₂OCH₃ H CH₂OH H OCH₃ OH HCH₂OH H OC₂H₅ OH H CH₂OH H OCH(CH₃)₂ OH H CH₂OH H OCH₂CH₂OCH₃ OH H CH₂OHH OCH₂CH₂CH₂OCH₃ OH H CH₂OH H OH OCH₃ H CH₂OH H OH OC₂H₅ H CH₂OH H OHOCH(CH₃)₂ H CH₂OH H OH OCH₂CH₂OCH₃ H CH₂OH H OH OCH₂CH₂CH₂OCH₃ H CH₂OH HOCH₃ OCH₃ H CH₂OH H OC₂H₅ OC₂H₅ H CH₂OH H OCH(CH₃)₂ OCH(CH₃)₂ H CH₂OH HOCH₂CH₂OCH₃ OCH₂CH₂OCH₃ H CH₂OH H OCH₂CH₂CH₂OCH₃ OCH₂CH₂CH₂OCH₃ H CH₃OCH₃ H OH H CH₃ OC₂H₅ H OH H CH₃ OCH(CH₃)₂ H OH H CH₃ OCH₂CH₂OCH₃ H OH HCH₃ OCH₂CH₂CH₂OCH₃ H OH H CH₃ OH H OCH₃ H CH₃ OH H OC₂H₅ H CH₃ OH HOCH(CH₃)₂ H CH₃ OH H OCH₂CH₂OCH₃ H CH₃ OH H OCH₂CH₂CH₂OCH₃ H CH₃ OCH₃ HOCH₃ H CH₃ OC₂H₅ H OC₂H₅ H CH₃ OCH(CH₃)₂ H OCH(CH₃)₂ H CH₃ OCH₂CH₂OCH₃ HOCH₂CH₂OCH₃ H CH₃ OCH₂CH₂CH₂OCH₃ H OCH₂CH₂CH₂OCH₃ H CH₂OH OCH₃ H OH HCH₂OH OC₂H₅ H OH H CH₂OH OCH(CH₃)₂ H OH H CH₂OH OCH₂CH₂OCH₃ H OH H CH₂OHOCH₂CH₂CH₂OCH₃ H OH H CH₂OH OH H OCH₃ H CH₂OH OH H OC₂H₅ H CH₂OH OH HOCH(CH₃)₂ H CH₂OH OH H OCH₂CH₂OCH₃ H CH₂OH OH H OCH₂CH₂CH₂OCH₃ H CH₂OHOCH₃ H OCH₃ H CH₂OH OC₂H₅ H OC₂H₅ H CH₂OH OCH(CH₃)₂ H OCH(CH₃)₂ H CH₂OHOCH₂CH₂OCH₃ H OCH₂CH₂OCH₃ H CH₂OH OCH₂CH₂CH₂OCH₃ H OCH₂CH₂CH₂OCH₃ H

[0064] And the salts of these compounds.

[0065] The compounds according to the invention can be prepared asdescribed by way of example in the following examples, or usinganalogous process steps starting from appropriate starting compounds(see, for example, EP-A-0 299 470 or Kaninski et al., J. Med. Chem.1985, 28, 876-892). The starting compounds are known or can be preparedanalogously to the known compounds. The compounds according to theinvention can be prepared for example starting from N-protected8-amino-imidazo[1,2-a]pyridines according to the following reactionscheme:

[0066] The above scheme represents an example of an enantioselectivesynthesis. The N-protected (Piv represents a customary protective group,preferably the pivaloyl group), 8-aminoimidazo[1,2-a]pyridinedeprotonated in the 7-position is reacted with an enantiomerically puredioxolane. This initially leads to a condensation product which can becyclized under strongly acidic conditions with removal of the protectinggroups. The subsequent reduction of the keto group using sodiumborohydride leads in over 90% enantiomeric purity to the 7,8-trans-diolindicated. The subsequent etherication which is carried out according toknown processes, e.g. as described in the Examples, leads to the finalproducts of formula I★ in which R2a and R3b are hydrogen. Thecorresponding 7,8-cis-compound is obtained from the mother liquor, whichis left after separating off the 7,8-trans-compound, by chromatographicpurification.

[0067] The substances according to the invention are isolated andpurified in a manner known per se, for example, by distilling off thesolvent in vacuo and recrystallizing the residue obtained from asuitable solvent or subjecting it to one of the customary purificationmethods; such as, for example, column chromatography on suitable supportmaterial.

[0068] Salts are obtained by dissolving the free compound in a suitablesolvent, e.g. in a chlorinated hydrocarbon, such as dichloromethane orchloroform, or a low molecular weight aliphatic alcohol (ethanol,isopropanol) which contains the desired acid, or to which the desiredacid is subsequently added. The salts are obtained by filtering,reprecipitating, precipitating with a nonsolvent for the addition saltor by evaporating the solvent. Salts obtained can be converted byalkalization or by acidification into the free compounds, which in turncan be converted into salts. In this way, pharmacologically intolerablesalts can be converted into pharmacologically tolerable salts.

[0069] The pure enantiomers, in particular the pure enantiomers of theformula I★, to which the invention preferably relates, can be obtainedin a manner familiar to the person skilled in the art, for example byenantioselective synthesis (see, for example, the Scheme), bychromatographic separation on chiral separating columns, byderivatization with chiral auxiliary reagents, subsequent separation ofdiastereomers and removal of the chiral auxiliary group, by saltformation with chiral adds, subsequent separation of the salts andliberation of the desired compound from the salt, or by (fractional)crystallization from a suitable solvent. Trans-products obtained (withR2a and R3b=hydrogen) can be converted (at least partly) to thecorresponding cis-products (with R2b and R3b=hydrogen) by standing underacidic conditions (e.g. 2 equivalents of acid, such as sulfuric acid) inthe corresponding alcohol R2a-OH. Likewise, cis-products obtained can beconverted to the corresponding trans-products. The cis- andtrans-products are separated e.g. by chromatography or bycrystallization.

[0070] The following examples serve to illustrate the invention furtherwithout restricting it. Likewise, further compounds of the formula Iwhose preparation is not described explicitly can be preparedanalogously or in a manner familiar to the person skilled in the artusing customary process techniques. The abbreviation min stands forminute(s), h for hour(s) and ee for enantiomeric excess.

EXAMPLES

[0071] Final Products

1A. (7R, 8R,9R)-2,3-Dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-[1,7]naphthyridine

[0072] Method a

[0073] 20 g (65 mmol) of (7R, 8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridineare dissolved in methanol (350 ml). 13.5 g of sulfuric acid are addedand the solution is stirred for 48 h at 50° C. After cooling thereaction mixture is poured into 250 ml of water. The pH is adjusted byaqueous saturated sodium hydrogen carbonate solution to neutral pH. Theprecipitate is collected and purified on silica gel (eluentdiethylether). 2.5 g of the title compound are obtained as colourlesscrystals of melting point 164-165° C. (2-propanol).

[0074] Method b

[0075] 10 g (32.5 mmol) of (7R, 8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridineare dissolved in 200 ml of dry dimethylformamide. 1.9 g of commerciallyavailable sodium hydride in paraffin (80%) are added in small portionsat room temperature. After 1 h 9.1 g (65 mmol) of methyl iodide,dissolved in 4 ml of dimethylformamide, are added and the mixture isstirred for an additional hour. The reaction mixture is poured into coldwater. 20 ml of a saturated aqueous ammonium chloride solution is added,the yellow precipitate is collected and discarded. The filtrate isextracted several times with ethyl acetate, the combined organic phasesare washed several times with water and the solvent is evaporated invacuo. The solid residue is purified an silica gel (diethylether). 2 gof the title compound are obtained as colourless crystals of meltingpoint 164-165° C. (2-propanol).

1B. (7S, 8S,9S)-2,3-Dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-[1,7]naphthyridine

[0076] The title compound of melting point 101-102° C. is obtainedsimilarly to the procedure described in Example 1, Method a, using(7S,8S,9S)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2h][1,7]naphthyridineas starting material.

2A. (7S, 8R,9R)-2,3-Dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-[1,7]naphthyridine

[0077] 6 g of the title compound are obtained as colourless powder ofmelting point 108-110° C. after purification on silica gel according toExample 1A, Method a, starting from(7S,8R,9R)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine.

2B. (7R, 8R,9S)-2,3-Dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-[1,7]naphthyridine

[0078] The title compound of melting point 171-172° C. is obtained fromthe mother liquor of Example 1B after purification on silica gel(eluent:diethyl ether).

3. (7R, 8R,9R)-2,3-Dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-[1,7]naphthyridine

[0079] 500 mg of the title compound are obtained by reaction of (7R, 8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridinewith ethanol and sulfuric acid according to Example 1, Method a, afterpurification on silica gel (eluent:diethylether). Melting point 188-190°C.

4. (7S, 8R,9R)-2,3-Dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-[1,7]naphthyridine

[0080] 800 mg of the title compound of melting point 135-137° C. areobtained as a solid by further purification of the mother liquor ofExample 3 on silica gel.

5A. (7R, 8R,9R)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine

[0081] Method a

[0082] 5 g of the title compound of melting point 130-1° C. are obtainedby reaction of 20 g (7R, 8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridinewith 2-methoxy-ethanol according to Example 1. Method a.

[0083] Method b

[0084] To a solution of 100 g of(7R,8R,9R)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo-[1,2h][1,7]naphthyridinein 1 l of 2-ethoxyethanol, 64 g of concentrated, sulfuric acid are addedslowly at room temperature under an argon atmosphere. The rate ofaddition is such that the temperature of the mixture does not exceed 35°C. After further 15 hours of stirring at room temperature the greenishsolution is poured into a mixture of 1 kg of crushed ice and 800 ml ofdichloromethane. The pH of the stirred mixture is adjusted to 7.5 byaddition of a 10 M aqueous sodium hydroxide solution, the organic layeris separated off, the aqueous layer is extracted three times withdichloromethane (200 ml each), the dichloromethane layers are washedcollectively with 500 ml of water (six times) and are then dried oversodium sulfate. After complete evaporation of the solvent under reducedpressure the remaining oily residue is treated with 450 ml of acetone toyield 75 g off-white crystals consisting of a 1:1 mixture of the titlecompound and its (7S, 8R, 9R)-epimer. The mixture is separated bypreparative HPLC using methanol as eluent 28 g of the title compound ofmelting point 128°-129° C. are obtained after recrystallization fromethyl acetate.

5B. (7S, 8S,9S)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine

[0085] The title compound of melting point 130°-131° C. is obtainedsimilarly to the procedure described in Example 5A, Method a, using (7S,8S,9S)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2h][1,7]naphthyridineas starting material.

6A. (7S, 8R,9R)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine

[0086] 7.8 g of the title compound of melting point 131-132° C. areobtained as a solid from the mother liquor of Example 5A afterpurification on silica gel (eluent:diethyl ether).

6B. (7R, 8S,9S)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine

[0087] The title compound of melting point 131°-132° C. is obtained fromthe mother liquor of Example 5B after purification on silica gel (eluentdiethyl ether).

7. (7S, 8R,9R)-2,3-Dimethyl-8-hydroxy-9-phenyl-7-(2-proproxy)-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine

[0088] 1 g of the title compound of melting point 168-9° C. is obtainedby reaction of 3 g of (7R, 8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridinewith 2-propanol according to Example 1, Method a.

8. (7R, 8R,9R)-2,3-Dimethyl-7,8-dimethoxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine

[0089] 8 g of the title compound of melting point 155-156° C. areobtained by reaction of 10 g of(7R,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridinewith 1.9 g of sodium hydride (80%) and 9.1 g of methyl iodide accordingto Example 1, Method b.

Starting Compounds A1. 2,3-Dimethyl-7-[(2R,3S)-2,3 Oisopropylidene-3-phenylpropan-1-on-1-yl]-8-pivaloylamino-imidazo[1,2-a]pyridine

[0090] 60 g (0.245 mol) of2,3-dimethyl-8-pivalylaminoimidazo[1,2-a]pyridine are dissolved in 1.5 lof anhydrous diethyl ether with exclusion of moisture and under an argonatmosphere and cooled to −75° C. By means of a flex needle; 408 ml(0.612 mol) of tert-butyllithium solution (1.5 M in n-pentane) are addeddropwise such that the temperature does not exceed −65° C. (30 min). Ared suspension is formed. After addition is complete, the suspension isstirred at −75° C. for further 30 min. ⅓ of a solution of 145 g ofmethyl (2R,3S)-2,3-O-isopropylidene-3-phenylpropionate (ee: 99.05%,Daicel Chiraicl HPLC) in 150 ml of dry THF is then slowly added dropwiseat a temperature below −65° C. during the course of 30 min. The residualquantity is then briskly added (5 min), a temperature rise to −60° C.taking place. After addition is complete the cooling bath is removed. Onreaching an internal temperature of −30° C. 20 ml of methanol are addedand at an internal temperature of 0° C. 200 ml of distilled water areadded. The aqueous phase is separated off in a separating funnel, theorganic phase is washed five times with 100 ml of distilled water eachtime, then the organic phase is extracted three times with 10% strengthsulfuric acid (200 ml, 50 ml, 50 ml). The sulfuric acid phases arecombined, treated with 200 ml of dichloromethane and adjusted to pH 2.3with 10N sodium hydroxide solution and with ice cooling and vigorousstirring. The organic layer is separated off. The aqueous phase isextracted with 30 ml of dichloromethane. The combined dichloromethanephases are washed twice with a little distilled water. The organic layeris then dried over anhydrous sodium sulfate and the solvent iscompletely stripped off in vacuo. A brown oil is obtained which istreated with 50 ml of diethyl ether. After seeding, crystals are formedwhich are filtered off after standing overnight and washed with diethylether. After drying in vacuo, 57.7 g (52.5%, ee>99%. Daicel ChiraicelHPLC) of the title compound of melting point 76-80° C. are obtained as apaie yellow powder.

A2.2,3-Dimethyl-7-[(2S,3R)-2,3-O-isopropylidene-3-phenylpropan-1-on-1-yl]-8-pivaloylamino-imidazo[1,2-a]pyridine.

[0091] The title compound (ee: 98.3%, Daicel Chiralcel HPLC) is obtainedsimilarly to the procedure described in example A1 by using methyl (2S,3R)-2,3-O-isopropylidene-3-phenylpropionate (ee: 98%, Dalcel ChiralcelHPLC) as acylating agent.

B1.(8R,9R)-2,3-Dimethyl-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine-7-one

[0092] 10.8 g (24 mmol) of2,3-dimethyl-7-[(2R,3S)-2,3-O-isopropylidene-3-phenylpropan-1-on1-yl]-8-pivaloylaminoimidazo[1,2-a]pyridine(ee>95%, Daicel Chiralcel HPLC) are introduced into 50 ml of 70%strength sulfuric acid with ice cooling during the course of 4 min. Asuspension is formed in the course of this, which turns into an orangesolution after 30 min. After addition is complete, the ice bath isremoved and the mixture is stirred on at mom temperature. The reactionsolution is added after 60 h to ice water and dichloromethane is added,then the mixture is adjusted to pH 8 using 6N sodium hydroxide solutionand saturated sodium hydrogen-carbonate solution. The organic phase isseparated off. The aqueous phase is extracted twice withdichloromethane. The organic phases are combined and washed with alittle distilled water. The organic layer is then dried over anhydroussodium sulfate, filtered and concentrated on a vacuum rotary evaporator.The concentrated residue is chromatographed an silica gel(eluent:dichloromethane/methanol 100/1). The main fraction isconcentrated and treated with ethyl acetate, and the title compoundcrystallizes in the course of this as a yellow solid. This precipitateis filtered off with suction and dried to constant weight in a vacuumdrying oven at 50° C. 4.22 g (57%, ee>95%, Daicel Chiralcel HPLC) of thetitle compound of melting point 231-4° C. are obtained.

B2.(8S,9S)-2,3-Dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine-7-one

[0093] The tile compound (ee: 94.0%. Daicel Chiralcel HPLC) is obtainedaccording to the procedure described in example 81 starting from2,3-dimethyl-7-[(2S,3R-2,3-O-isopropylidene-3-phenylpropan-1-on-1-yl]-8-pivaloylaminoimidazo[1,2-a]pyridine.

C1.(7R,8,R9R)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2h][1,7]-naphthyridine

[0094] 6 g (19.52 mmol) of (8R,9R)-2,3-dimethyl 8hydroxy-9-phenyl-7,8,9,10-tetra-hydroimidazo-[1,2-h][1,7]naphthyridine-7-one(ee>90%, Daicel Chiraicel HPLC) are suspended in 60 ml of methanol andcooled to −5° to 0° C. in a methanol-ice bath. At this temperature,sodium borohydride (0.81 g, 21.47 mmol) is added by spatula during thecourse of 0.5 h (evolution of gas). After addition is complete, themixture is stirred for a further 10 min, and then concentrated in avacuum rotary evaporator at a bath temperature of 40° C. The oilyresidue obtained is taken up in distilled water and extracted threetimes with chloroform. The organic phases are combined and washed with alittle water, then dried using anhydrous sodium sulfate and filtered.The filtrate is concentrated on a vacuum rotary evaporator andco-evaporated with acetone; the title compound crystallizes out in thecourse of this. The precipitate is filtered off, washed with acetone anddried to constant weight at 50° C. in a vacuum drying oven. 5.15 g(85.3%. ee>90%, Daicel Chiralcel HPLC) of the title compound areobtained as a colorless crystallizate of melting point 208-9° C.

C2. (7S, 8S,9S)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2h][1,7]-naphthyridine

[0095] The title compound of mp 207-208° C. (ee: 98.7%, Daicel ChiralcelHPLC) is obtained according to the procedure described in example C1using (8S,9S)-2,3-dimethyl-8-hydroxy9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-oneas starting material.

D. (7S, 8R,9R)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine

[0096] 2 g of the mother liquor of Example C1 are chromatographed onsilica gel (eluent:ethyl acetate/methanol 19/1) to give 0.35 g of thetitle compound as an oil which crystallizes upon addition of ethylacetate. Melting point.: 199-200° C. (ethyl acetate).

Commercial Utility

[0097] The compounds of the formula I and their salts have usefulpharmacological properties which make them commercially utilizable. Inparticular, they exhibit a marked inhibition of gastric acid secretionand an excellent gastric and intestinal protective action inwarm-blooded animals, in particular humans. In this context, thecompounds according to the invention are distinguished by a highselectivity of action, an advantageous duration of action, aparticularly good enteral activity, the absence of significant sideeffects and a large therapeutic breadth.

[0098] “Gastric and intestinal protection” in this connection isunderstood as meaning the prevention and treatment of gastrointestinaldiseases, in particular of gastrointestinal inflammatory diseases andlesions (such as, for example, stomach ulcers, duodenal ulcers,gastritis, hyperacidic or medicament-related functional gastropathy),which can be caused, for example, by microorganisms (e.g. Helicobacterpylori), bacterial toxins, medicaments (e.g. certain antiinflammatoriesand antirheumatics), chemicals (e.g. ethanol), gastric acid or stresssituations.

[0099] In their excellent properties, the compounds according to theinvention surprisingly prove to be clearly superior to the compoundsknown from the prior art in various models in which the antiulcerogenicand the antisecretory properties are determined. On account of theseproperties, the compounds of the formula I and their pharmacologicallytolerable salts are outstandingly suitable for use in human andveterinary medicine, where they are used, in particular, for thetreatment and/or prophylaxis of disorders of the stomach and/orintestine.

[0100] The invention therefore further relates to the compoundsaccording to the invention for use in the treatment and/or prophylaxisof the abovementioned diseases.

[0101] The invention likewise comprises the use of the compoundsaccording to the invention for the production of medicaments which areemployed for the treatment and/or prophylaxis of the abovementioneddiseases.

[0102] The invention furthermore comprises the use of the compoundsaccording to the invention for the treatment and/or prophylaxis of theabovementioned diseases.

[0103] The invention furthermore relates to medicaments which containone or more compounds of the formula I and/or their pharmacologicallytolerable salts.

[0104] The medicaments are prepared by processes known per se, which arefamiliar to the person skilled in the art. As medicaments, thepharmacologically active compounds according to the invention (=activecompounds) are employed either as such, or preferably in combinationwith suitable pharmaceutical auxiliaries or excipients in the form oftablets, coated tablets, capsules, suppositories, patches (e.g. as TTS),emulsions, suspensions or solutions, where the active compound contentis advantageously between 0.1 and 95% and where, by the appropriatechoice of the auxiliaries and excipients, a pharmaceuticaladministration form (e.g. a delayed-release form or an enteric form)exactly suited to the active compound and/or to the desired onset ofaction can be achieved.

[0105] The person skilled in the art is familiar, on the basis of hisexpert knowledge, with auxiliaries or excipients which are suitable forthe desired pharmaceutical formulations. Beside solvents, gel-formingagents, suppository bases, tablet auxiliaries and other active compoundcarriers, it is possible to use, for example, antioxidants, dispersants,emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers,colorants or, in particular, permeation promoters and complexing agents(e.g. cyclodextrins).

[0106] The active compounds can be administered orally, parenterally orpercutaneously.

[0107] In general, it has proven advantageous in human medicine toadminister the active compound(s) in the case of oral administration ina daily dose from approximately 0.01 to approximately 20, preferably0.05 to 5, in particular 0.1 to 1.5, mg/kg of body weight, ifappropriate in the form of several, preferably 1 to 4, individual dosesto achieve the desired result. In the case of parenteral treatment,similar or (in particular in the case of intravenous administration ofthe active compounds), as a rule, lower doses can be used. The optimaldose and manner of administration of the active compounds necessary ineach case can easily be determined by any person skilled in the art onthe basis of his expert knowledge.

[0108] If the compounds according to the invention and/or their saltsare to be employed for the treatment of the abovementioned diseases, thepharmaceutical preparations can also contain one or morepharmacologically active constituents of other pharmaceutical groups.Examples which may be mentioned are: tranquilizers (for example from thebenzodiazapines group, e.g. diazepam), spasmolytics (e.g. bietamiverineor camylofin), anticholinergics (e.g. oxyphencyclimine orphencarbamide), local anesthetics (e.g. tetracaine or procaine), and, ifappropriate, also enzymes, vitamins or amino acids.

[0109] To be emphasized in this connection, in particular, is thecombination of the compounds according to the invention withpharmaceuticals which inhibit acid secretion, such as, for example, H2blockers (e.g. cimetidine, ranitidine), H+/K+− ATPase inhibitors (e.g.omeprazole, paritoprazole), or furthermore with so-called peripheralanticholinergics (e.g. pirenzepine, telenzepine), and with gastrinantagonists with the aim of increasing the main action in, an additiveor superadditive sense and/or of eliminating or decreasing the sideeffects, or furthermore the combination with antibacterially activesubstances (e.g. cephalosporins, tetracyclines, penicllins, macrolides,nitroimidazoles or alternatively bismuth salts) for the control ofHelicobacter pylori. Antbaterially active combination components whichmay be mentioned are, for example, mezlocillin, ampicillin, amoxycillin,cefalothin, cefoxtin, cefotaxime, imipenem, gentamycin, amikacin,arythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycinand combinations thereof (e.g. clarithromycin+metronidazole).

Pharmacology

[0110] The excellent gastric protective action and the gastric acidsecretion-inhibiting action of the compounds according to the inventioncan be demonstrated in animal experimental models. The compoundsaccording to the invention investigated in the model mentioned belowhave been provided with numbers which correspond to the numbers of thesecompounds in the examples.

[0111] Testing of the Secretion-Inhibiting Action on the Perfused RatStomach

[0112] Table A below shows the effects of the compounds according to theinvention on the pentagastrin-stimulated acid secretion of the perfusedrat stomach in vivo after intravenous administration. TABLE A DoseInhibition of acid (μmol/kg) secretion No. i.v. (%) 1 3 100 2 3 100 3 3100 4 3 100 5 3 100 6 3 100 7 3 100 8 3 100

[0113] Methodology

[0114] The abdomen of anesthetized rats (CD rat, female, 200-250 g; 1.5g/kg i.m. urethane) was opened after tracheotomy by means of a medianupper abdominal incision and a PVC catheter was fixed transorally in theesophagus and another via the pylorus such that the ends of the tubejust projected into the gastric lumen. The catheter leading from thepylorus led outwards Into the right abdominal wall through a sideopening.

[0115] After thorough rinsing (about 50-100 ml), warm physiological NaClsolution at 37° C. was continuously passed through the stomach (0.5ml/min, pH 6.8-6.9; Braun-Unita I). The pH (pH meter 632, glasselectrode EA 147; φ=5 mm, Metrohm) and, by titration with a freshlyprepared 0.01 N NaOH solution to pH 7 (Dosimat 665 Metrohm), thesecreted HCl were determined in the effluent in each case collected atan interval of 15 minutes.

[0116] The gastric secretion was stimulated by continuous infusion or 1μg/kg (=1.65 ml/h) of i.v. pentagastrin (left femoral vein) about 30 minafter the end of the operation (i.e. other determination of 2preliminary tractions). The substances to be tested were administratedintravenously in 1 ml/kg liquid volumes 60 min after the start of thepentagastrin continuous infusion.

[0117] The body temperature of the animals was kept at a constant37.8-38° C. by infrared irradiation and heat pads (automatic, steplesscontrol by means of a rectal temperature sensor).

1. A compound of formula 1*

wherein R1 is CH₃; each of R2a and R3b is H; and each of R2b and R3a isa member selected from the group consisting of OH, OCH₃, OCH(CH₃)₂,OCH₂CH₂CH₃, and OCH₂CH₂CH₂OCH₃; with the provisos that both R2b and R3aare not concurrently OH, and that, when neither is OH, both are thesame.
 2. The compound of claim 1 wherein R2b is OH, and R3a is OCH₃. 3.The compound of claim 1 wherein R2b is OH, and R3a is OCH₂CH₃.
 4. Thecompound of claim 1 wherein R2b is OH, and R3a is OCH(CH₃)₂.
 5. Thecompound of claim 1 wherein R2b is OH, and R3a is OCH₂CH₂CH₃.
 6. Thecompound of claim 1 wherein R2b is OH, and R3a is OCH₂CH₂CH₂OCH₃.
 7. Thecompound of claim 1 wherein R3a is OH, and R2b is OCH₃.
 8. The compoundof claim 1 wherein R3a is OH, and R2b is OCH₂CH₃.
 9. The compound ofclaim 1 wherein R3a is OH, and R2b is OCH(CH₃)₂.
 10. The compound ofclaim 1 wherein R3a is OH, and R2b is OCH₂CH₂CH₃.
 11. The compound ofclaim 1 wherein R3a is OH, and R2b is OCH₂CH₂CH₂OCH₃.
 12. The compoundof claim 1 wherein R2b and R3a is OCH₃.
 13. The compound of claim 1wherein R2b and R3a is OCH₂CH₃.
 14. The compound of claim 1 wherein R2band R3a is OCH(CH₃)₂.
 15. The compound of claim 1 wherein R2b and R3a isOCH₂CH₂CH₃.
 16. The compound of claim 1 wherein R2b and R3a isOCH₂CH₂CH₂OCH₃.
 17. A compound of claim 1 which is in the form of apharmaceutically acceptable salt.
 18. A compound of formula 1*

wherein R1 is CH₂OH; each of R2a and R3b is H; and each of R2b and R3ais a member selected from the group consisting of OH, OCH₃, OCH(CH₃)₂,OCH₂CH₂CH₃, and OCH₂CH₂CH₂OCH₃; with the provisos that both R2b and R3aare not concurrently OH, and that, when neither is OH, both are thesame.
 19. The compound of claim 18 wherein R2b is OH, and R3a is OCH₃.20. The compound of claim 18 wherein R2b is OH, and R3a is OCH₂CH₃. 21.The compound of claim 18 wherein R2b is OH, and R3a is OCH(CH₃)₂. 22.The compound of claim 18 wherein R2b is OH, and R3a is OCH₂CH₂CH₃. 23.The compound of claim 18 wherein R2b is OH, and R3a is OCH₂CH₂CH₂OCH₃.24. The compound of claim 18 wherein R3a is OH, and R2b is OCH₃.
 25. Thecompound of claim 18 wherein R3a is OH, and R2b is OCH₂CH₃.
 26. Thecompound of claim 18 wherein R3a is OH, and R2b is OCH(CH₃)₂.
 27. Thecompound of claim 18 wherein R3a is OH, and R2b is OCH₂CH₂CH₃.
 28. Thecompound of claim 18 wherein R3a is OH, and R2b is OCH₂CH₂CH₂OCH₃. 29.The compound of claim 18 wherein R2b and R3a is OCH₃.
 30. The compoundof claim 18 wherein R2b and R3a is OCH₂CH₃.
 31. The compound of claim 18wherein R2b and R3a is OCH(CH₃)₂.
 32. The compound of claim 18 whereinR2b and R3a is OCH₂CH₂CH₃.
 33. The compound of claim 18 wherein R2b andR3a is OCH₂CH₂CH₂OCH₃.
 34. A compound of claim 18 which is in the formof a pharmaceutically acceptable salt.
 35. A compound of formula 1*

wherein R1 is CH₃; each of R2b and R3b is H; and each of R2a and R3a isa member selected from the group consisting of OH, OCH₃, OCH(CH₃)₂,OCH₂CH₂CH₃, and OCH₂CH₂CH₂OCH₃; with the provisos that both R2a and R3aare not concurrently OH, and that, when neither is OH, both are thesame.
 36. The compound of claim 35 wherein R2b is OH, and R3a is OCH₃.37. The compound of claim 35 wherein R2b is OH, and R3a is OCH₂CH₃. 38.The compound of claim 35 wherein R2b is OH, and R3a is OCH(CH₃)₂. 39.The compound of claim 35 wherein R2b is OH, and R3a is OCH₂CH₂CH₃. 40.The compound of claim 35 wherein R2b is OH, and R3a is OCH₂CH₂CH₂OCH₃.41. The compound of claim 35 wherein R3a is OH, and R2b is OCH₃.
 42. Thecompound of claim 35 wherein R3a is OH, and R2b is OCH₂CH₃.
 43. Thecompound of claim 35 wherein R3a is OH, and R2b is OCH(CH₃)₂.
 44. Thecompound of claim 35 wherein R3a is OH, and R2b is OCH₂CH₂CH₃.
 45. Thecompound of claim 35 wherein R3a is OH, and R2b is OCH₂CH₂CH₂OCH₃. 46.The compound of claim 35 wherein R2b and R3a is OCH₃.
 47. The compoundof claim 35 wherein R2b and R3a is OCH₂CH₃.
 48. The compound of claim 35wherein R2b and R3a is OCH(CH₃)₂.
 49. The compound of claim 35 whereinR2b and R3a is OCH₂CH₂CH₃.
 50. The compound of claim 35 wherein R2b andR3a is OCH₂CH₂CH₂OCH₃.
 51. A compound of claim 35 which is in the formof a pharmaceutically acceptable salt.
 52. A compound of formula 1*

wherein R1 is CH₂OH; each of R2b and R3b is H; and each of R2a and R3ais a member selected from the group consisting of OH, OCH₃, OCH(CH₃)₂,OCH₂CH₂CH₃, and OCH₂CH₂CH₂OCH₃; with the provisos that both R2a and R3aare not concurrently OH, and that, when neither is OH, both are thesame.
 53. The compound of claim 52 wherein R2b is OH, and R3a is OCH₃.54. The compound of claim 52 wherein R2b is OH, and R3a is OCH₂CH₃. 55.The compound of claim 52 wherein R2b is OH, and R3a is OCH(CH₃)₂. 56.The compound of claim 52 wherein R2b is OH, and R3a is OCH₂CH₂CH₃. 57.The compound of claim 52 wherein R2b is OH, and R3a is OCH₂CH₂CH₂OCH₃.58. The compound of claim 52 wherein R3a is OH, and R2b is OCH₃.
 59. Thecompound of claim 52 wherein R3a is OH, and R2b is OCH₂CH₃.
 60. Thecompound of claim 52 wherein R3a is OH, and R2b is OCH(CH₃)₂.
 61. Thecompound of claim 52 wherein R3a is OH, and R2b is OCH₂CH₂CH₃.
 62. Thecompound of claim 52 wherein R3a is OH, and R2b is OCH₂CH₂CH₂OCH₃. 63.The compound of claim 52 wherein R2b and R3a is OCH₃.
 64. The compoundof claim 52 wherein R2b and R3a is OCH₂CH₃.
 65. The compound of claim 52wherein R2b and R3a is OCH(CH₃)₂.
 66. The compound of claim 52 whereinR2b and R3a is OCH₂CH₂CH₃.
 67. The compound of claim 52 wherein R2b andR3a is OCH₂CH₂CH₂OCH₃.
 68. A compound of claim 52 which is in the formof a pharmaceutically acceptable salt.